When subsequent exposures to a drug provoke a stronger response than the first exposure, sensitization has occurred.1 Some sensitized responses are observable behaviors such as locomotion, while others are not, such as increased burst firing of dopamineric neurons.2 Despite differences in their pharmacological effects and sites of action, nicotine, morphine, alcohol, cocaine, amphetamine and methamphetamine are all sensitizing drugs.3- 8 For over 70 years, scientists have conducted animal experiments to examine the role of sensitization in addiction.1 However, unlike rodents, humans do not display locomotor or other apparent behavioral manifestations of sensitization. We developed a new restraint that allows us to perform functional magnetic resonance imaging (fMRI) on fully awake animals to study drugs of abuse.9-13 We have demonstrated that neural sensitization to nicotine can be imaged in rodents using fMRI with blood oxygen level dependent (BOLD) contrast. A sensitized neural response manifests as a positive BOLD signal of greater magnitude in the hippocampus, ventral tegmentum, septum and prefrontal cortex, and as a protracted response in these regions as well as the nucleus accumbens and ventral pallidum. Neural sensitization is observed even though the animals are prevented from expressing a motor response because they are kept immobile in the MRI scanner. Therefore, neural sensitization may be detected in humans even if humans do not display sensitized behavior. The aim of this project is to determine if fMRI with BOLD contrast can be used to visualize nicotine sensitization in humans. We will compare the effects on BOLD contrast of a small dose of nicotine in nicotine- naive subjects and in smokers. Subjects will remain abstinent from nicotine for 27 hours prior to imaging to allow any nicotinic receptor desensitization to resolve. We hypothesize that neural sensitization will be evident in smokers as an augmented BOLD response in several limbic system structures compared to nonsmokers. We hypothesize that the specificity of this response will be demonstrated by the absence of any difference between groups in BOLD response in the visual cortex. The development of a technique for imaging sensitization in humans will make it feasible to (1) use sensitization of BOLD response in animals as a model of addiction in humans; (2) conduct parallel sensitization experiments in humans and animals with the addition of invasive methods such as microdialysis and ablation in animals; (3) perform experiments to test competing theories of addiction; (4) study human sensitization to all drugs of abuse to identify common mechanisms; (5) evaluate the dependence liability of new drugs; and (6) identify new targets for the development of drugs to treat addiction. The long-term goal of this multi-disciplinary collaboration is to translate animal research to a human application for the possible treatment of addiction. Significance All addictive drugs trigger a change in brain function called sensitization. Recent technical advances in functional MRI enable us to visualize sensitization to nicotine in rats. Our goal is to determine if MRI can image sensitization in smokers' brains, if so, it may be possible to image human sensitization to all addictive drugs. The long-term goal is to use this new tool to see how addictive drugs alter the brain, and thereby identify targets for the development of new drugs to treat addiction. [unreadable] [unreadable] [unreadable]